Compositions Comprising Sphingosine 1 Phosphate (S1P) Receptor Modulators

ABSTRACT

The present invention relates to stable compositions comprising a sphingosine 1 phosphate (S1P) receptor modulator, suitable for use as a dosage form. The S1P receptor modulators are typically sphingosine analogues, such as 2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives, e. g. a compound comprising a group of formula Y.

The present invention relates to a composition comprising a sphingosine1 phosphate (S1P) receptor modulator.

In particular, the present invention relates to stable compositionscomprising a sphingosine 1 phosphate (S1P) receptor modulator suitablefor use as a dosage form.

S1P receptor modulators are typically sphingosine analogues, such as2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives,e. g. a compound comprising a group of formula Y.

S1P Receptor Modulators

Sphingosine-1 phosphate (hereinafter “S1P”) is a natural serum lipid.Presently there are eight known S1P receptors, namely S1P1 to S1P8. S1Preceptor modulators are typically sphingosine analogues, such as2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives,e. g. a compound comprising a group of formula Y

wherein Z is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, phenylsubstituted by OH, C₁₋₆alkyl substituted by 1 to 3 substituents selectedfrom the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenylsubstituted by OH, or CH₂—R_(4z) wherein R_(4z) is OH, acyloxy or aresidue of formula (a)

wherein Z₁ is a direct bond or O, preferably O;

each of R_(5z) and R_(6z), independently, is H, or C₁₋₄alkyl optionallysubstituted by 1, 2 or 3 halogen atoms;

R_(1z) is OH, acyloxy or a residue of formula (a); and each of R_(2z)and R_(3z) independently, is H, C₁₋₄alkyl or acyl.

Group of formula Y is a functional group attached as a terminal group toa moiety which may be hydrophilic or lipophilic and comprise one or morealiphatic, alicyclic, aromatic and/or heterocyclic residues, to theextent that the resulting molecule wherein at least one of Z and R_(1z)is or comprises a residue of formula (a), signals as an agonist at oneof more sphingosine-1-phosphate receptor.

S1P receptor modulators are compounds which signal as agonists at one ormore sphingosine-1 phosphate receptors, e.g. S1P1 to S1P8. Agonistbinding to a S1P receptor may e.g. result in dissociation ofintracellular heterotrimeric G-proteins into Gα-GTP and Gβγ-GTP, and/orincreased phosphorylation of the agonist-occupied receptor andactivation of downstream signaling pathways/kinases.

Examples of appropriate S1P receptor modulators, comprising a group offormula Y are, for example:

Compounds as disclosed in EP627406A1, e.g. a compound of formula I

wherein R₁ is a straight- or branched (C₁₂₋₂₂)chain

-   -   which may have in the chain a bond or a hetero atom selected        from a double bond, a triple bond, O, S, NR₆, wherein R₆ is H,        C₁₋₄alkyl, aryl-C₁₋₄alkyl, acyl or (C₁₋₄alkoxy)carbonyl, and        carbonyl, and/or        -   which may have as a substituent C₁₋₄alkoxy, C₂₋₄alkenyloxy,            C₂₋₄alkynyloxy, arylC₁₋₄alkyl-oxy, acyl, C₁₋₄alkylamino,            acylamino, (C₁₋₄alkoxy)carbonyl, (C₁₋₄alkoxy)-carbonylamino,            acyloxy, (C₁₋₄alkyl)carbamoyl, nitro, halogen, amino,            hydroxyimino, hydroxy or carboxy; or

R₁ is

-   -   a phenylalkyl wherein alkyl is a straight- or branched        (C₆₋₂₀)carbon chain; or    -   a phenylalkyl wherein alkyl is a straight- or branched        (C₁₋₃₀)carbon chain wherein said phenylalkyl is substituted by    -   a straight- or branched (C₆₋₂₀)carbon chain optionally        substituted by halogen,    -   a straight- or branched (C₆₋₂₀)alkoxy chain optionally        substituted by halogen,    -   a straight- or branched (C₆₋₂₀)alkenyloxy,    -   phenyl-C₁₋₁₄alkoxy, halophenyl-C₁₋₄alkoxy,        phenyl-C₁₋₁₄alkoxy-C₁₋₁₄alkyl, phenoxy-C₁₋₄alkoxy or        phenoxy-C₁₋₄alkyl,    -   cycloalkylalkyl substituted by C₆₋₂₀alkyl,    -   heteroarylalkyl substituted by C₆₋₂₀alkyl,    -   heterocyclic C₆₋₂₀alkyl or    -   heterocyclic alkyl substituted by C₂₋₂₀alkyl,

and wherein

the alkyl moiety may have

-   -   in the carbon chain, a bond or a heteroatom selected from a        double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR₆,        wherein R₆ is as defined above, and    -   as a substituent C₁₋₄alkoxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy,        arylC₁₋₄alkyloxy, acyl, C₁₋₄alkyl-amino, C₁₋₄alkylthio,        acylamino, (C₁₋₄alkoxy)carbonyl, (C₁₋₄alkoxy)carbonylamino,        acyloxy, (C₁₋₄alkyl)carbamoyl, nitro, halogen, amino, hydroxy or        carboxy, and each of R₂, R₃, R₄ and R₅, independently, is H,        C₁₋₄ alkyl or acyl or a pharmaceutically acceptable salt or        hydrate thereof;

Compounds as disclosed in EP 1002792A1, e.g. a compound of formula II

wherein m is 1 to 9 and each of R′₂, R′₃, R′₄ and R′₅, independently, isH, C₁₋₆alkyl or acyl, or a pharmaceutically acceptable salt or hydratethereof;

-   -   Compounds as disclosed in EP0778263 A1, e.g. a compound of        formula III

wherein W is H; C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; unsubstituted orby OH substituted phenyl; R″₄O(CH₂)_(n); or C₁₋₆alkyl substituted by 1to 3 substituents selected from the group consisting of halogen,C₃₋₈cycloalkyl, phenyl and phenyl substituted by OH;

X is H or unsubstituted or substituted straight chain alkyl having anumber p of carbon atoms or unsubstituted or substituted straight chainalkoxy having a number (p-1) of carbon atoms, e.g. substituted by 1 to 3substitutents selected from the group consisting of C₁₋₆alkyl, OH,C₁₋₆alkoxy, acyloxy, amino, C₁₋₆alkylamino, acylamino, oxo,haloC₁₋₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH,C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino,haloC₁₋₆alkyl and halogen; Y is H, C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl,acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl or halogen, Z₂is a single bond or a straight chain alkylene having a number or carbonatoms of q,

each of p and q, independently, is an integer of 1 to 20, with theproviso of 6≦p+q≦23, m′ is 1, 2 or 3, n is 2 or 3,

each of R″₁, R″₂, R″₃ and R″₄, independently, is H, C₁₋₄alkyl or acyl,or a pharmaceutically acceptable salt or hydrate thereof,

Compounds as disclosed in WO02/18395, e.g. a compound of formula IVa orIVb

wherein X, is O, S, NR_(1s) or a group —(CH₂)_(na)—, which group isunsubstituted or substituted by 1 to 4 halogen; n_(a) is 1 or 2, R_(1s)is H or (C₁₋₄ alkyl, which alkyl is unsubstituted or substituted byhalogen; R_(1a) is H, OH, (C₁₋₄)alkyl or O(C₁₋₄)alkyl wherein alkyl isunsubstituted or substituted by 1 to 3 halogen; R_(1b) is H, OH or(C₁₋₄)alkyl, wherein alkyl is unsubstituted or substituted by halogen;each R_(2a) is independently selected from H or (C₁₋₄)alkyl, which alkylis unsubstituted or substituted by halogen; R_(3a) is H, OH, halogen orO(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen;and R_(3b) is H, OH, halogen, (C₁₋₄)alkyl wherein alkyl is unsubstitutedor substituted by hydroxy, or O(C₁₋₄)alkyl wherein alkyl isunsubstituted or substituted by halogen; Y_(a) is —CH₂—, —C(O)—,—CH(OH)—, —C(═NOH)—, O or S, and R_(4a) is

(C₄₋₁₄)alkyl or (C₄₋₁₄)alkenyl;

or a pharmaceutically acceptable salt or hydrate thereof;

Amino Alcohol Compounds of Formula V

wherein X is O, S, SO or SO₂;

R₁ is halogen, trihalomethyl, OH, C₁₋₇alkyl, C₁₋₄alkoxy,trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy,cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH₂—OH, CH₂—CH₂—OH,C₁₋₄alkylthio, C₁₋₄alkylsulfonyl, benzylthio, acetyl, nitro or cyano, orphenyl, phenylC₁₋₄alkyl or phenyl-C₁₋₄alkoxy each phenyl group thereofbeing optionally substituted by halogen, CF₃, C₁₋₄alkyl or C₁₋₄alkoxy;

R₂ is H, halogen, trihalomethyl, C₁₋₄alkoxy, phenethyl or benzyloxy;

R₃H, halogen, CF₃, OH, C₁₋₇alkyl, C₁₋₄alkoxy, benzyloxy, phenyl orC₁₋₄alkoxymethyl; each of R₄ and R₅, independently is H or a residue offormula (a)

wherein each of R₈ and R₉, independently, is H or C₁₋₄alkyl optionallysubstituted by halogen; and

n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof;

or a compound of formula VI

wherein

-   R_(1a) is halogen, trihalomethyl, C₁₋₄alkoxy, C₁₋₄alkylthio,    C₁₋₄alkylsulfinyl, sulfonyl, aralkyl, optionally substituted phenoxy    or aralkyloxy;-   R_(2a) is H, halogen, trihalomethyl, C₁₋₄alkyl, C₁₋₄alkoxy, aralkyl    or aralkyloxy;-   R_(3a) is H, halogen, CF₃, C₁₋₄alkoxy, C₁₋₄alkylthio or benzyloxy;-   R_(4a) is H, C₁₋₄alkyl, phenyl, optionally substituted benzyl or    benzoyl, or lower aliphatic C₁₋₅acyl;-   R_(5a) is H, monohalomethyl, C₁₋₄alkoxy-methyl,    C₁₋₄alkyl-thiomethyl, hydroxyethyl, hydroxypropyl, phenyl, aralkyl,    C₂₋₄alkenyl or -alkynyl;-   R_(6a) is H or C₁₋₄alkyl;-   R_(7a) is H, C₁₋₄alkyl or a residue of formula (a) as defined above,-   X_(a) is O, S, SO or SO₂; and-   n_(a) is an integer of 1 to 4;-   or a pharmaceutically acceptable salt thereof.

With regard to the compounds of formulae (I) and (II), the term“halogen” encompasses fluorine, chlorine, bromine and iodine. The term“trihalomethyl group” encompasses trifluoromethyl and trichloromethyl.“C₁₋₇ alkyl” encompasses straight-chained or branched alkyl, e.g.methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl orheptyl. The phrase “substituted or unsubstituted phenoxy group”encompasses those that have, at any position of its benzene ring, ahalogen atom, such as fluorine, chlorine, bromine and iodine,trifluoromethyl, C₁₋₄alkyl or C₁₋₄alkoxy. The term “aralkyl group” as in“aralkyl group” or “aralkyloxy group” encompasses benzyl,diphenylmethyl, phenethyl and phenylpropyl. Any alkyl moiety as presentin “C₁₋₄alkoxy”, “C₁₋₄alkylthio”, “C₁₋₄alkylsulfinyl” or“C₁₋₄alkylsulfonyl encompasses straight-chained or branched C₁₋₄alkyl,e.g. methyl, ethyl, propyl, isopropyl or butyl. The phrase “substitutedor unsubstituted aralkyl group” encompasses those that have, at anyposition of its benzene ring, a halogen atom, such as fluorine,chlorine, bromine and iodine, trifluoromethyl, lower alkyl having 1-4carbon atoms, or lower alkoxy having 1-4 carbon atoms.

Other compounds of formula V are compounds of formula Va

wherein

R₂, R₃, R₄, R₅ and n are as defined above; and Y is O or S and

R₆ is hydrogen, halogen, C₁₋₇alkyl, C₁₋₄alkoxy or trifluoromethyl.

Compounds of formulae V and Va are known and are disclosed e.g. inWO03/029205, WO 03/029184 and WO04/026817, respectively, thephosphorylated derivatives being disclosed e.g. in WO04/074297, thecontents of which being incorporated herein by reference in theirentirety. Compounds disclosed may be prepared as disclosed in the citedreferences herein.

Phosphorylated derivatives of compounds described herein can be preparedutilizing the procedures for synthesizing phosphorylated compoundsdescribed known in the art, e.g., in WO 2005/021503 (see, e.g., pages 11and 12).

Optically active compounds of and phosphorylated derivatives thereof canbe prepared in high purity utilizing procedure described in the art,e.g. in Hinterding et al., Synthesis, Vol. 11, pp. 1667-1670 (2003).

Compounds as disclosed in WO02/06268A1, e.g. a compound of formula VI

wherein each of R_(1d) and R_(2d), independently, is H or anamino-protecting group;

R_(3d) is hydrogen, a hydroxy-protecting group or a residue of formula

R_(4d) is C₁₋₄alkyl;

n_(d) is an integer of 1 to 6;

X_(d) is ethylene, vinylene, ethynylene, a group having a formula-D-CH₂— (wherein D is carbonyl, —CH(OH)—, O, S or N), aryl or arylsubstituted by up to three substituents selected from group a as definedhereinafter;

Y_(d) is single bond, C₁₋₁₀alkylene, C₁₋₁₀alkylene which is substitutedby up to three substituents selected from groups a and b, C₁₋₁₀alkylenehaving O or S in the middle or end of the carbon chain, or C₁₋₁₀alkylenehaving O or S in the middle or end of the carbon chain which issubstituted by up to three substituents selected from groups a and b;R_(5d) is hydrogen, C₃₋₆cycloalkyl, aryl, heterocyclic group,C₃₋₆cycloalkyl substituted by up to three substituents selected fromgroups a and b, aryl substituted by up to three substituents selectedfrom groups a and b, or heterocyclic group substituted by up to threesubstituents selected from groups a and b;

each of R_(6d) and R_(7d), independently, is H or a substituentsselected from group a;

each of R_(8d) and R_(9d), independently, is H or C₁₋₄alkyl optionallysubstituted by halogen;

<group a> is halogen, lower alkyl, halogeno lower alkyl, lower alkoxy,lower alkylthio, carboxyl, lower alkoxycarbonyl, hydroxy, loweraliphatic acyl, amino, mono-lower alkylamino, acylamino, cyano or nitro;and

<group b> is C₃₋₆cycloalkyl, aryl or heterocyclic group, each beingoptionally substituted by up to three substituents selected from groupa;

with the proviso that when R_(5d) is hydrogen, Y_(d) is a either asingle bond or linear C₁₋₁₀ alkylene, or a pharmacologically acceptablesalt, ester or hydrate thereof;

-   -   Compounds as disclosed in JP-14316985 (JP2002316985), e.g. a        compound of formula VII

wherein R_(1e), R_(2e), R_(3e), R_(4e), R_(5e), R_(6e), R_(7e), n_(e),X_(e) and Y_(e) are as disclosed in JP-14316985;

or a pharmacologically acceptable salt, ester or hydrate thereof;

-   -   Compounds as disclosed in WO03/062252A1, e.g. a compound of        formula VIII

wherein

Ar is phenyl or naphthyl; each of m_(g) and n_(g) independently is 0 or1; A is selected from COOH, PO₃H₂, PO₂H, SO₃H, PO(C₁₋₃alkyl)OH and1H-tetrazol-5-yl; each of R_(1g) and R_(2g) independently is H, halogen,OH, COOH or C₁₋₄alkyl optionally substituted by halogen; R₃₉ is H orC₁₋₄alkyl optionally substituted by halogen or OH; each R_(4g)independently is halogen, or optionally halogen substituted C₁₋₄alkyl orC₁₋₃alkoxy; and each of R_(g) and M has one of the significances asindicated for B and C, respectively, in WO03/062252A1; or apharmacologically acceptable salt, solvate or hydrate thereof;

-   -   Compounds as disclosed in WO 03/062248A2, e.g. a compound of        formula IX

wherein Ar is phenyl or naphthyl; n is 2, 3 or 4; A is COOH,1H-tetrazol-5-yl, PO₃H₂, PO₂H₂, —SO₃H or PO(R_(5h))OH wherein R_(5h) isselected from C₁₋₄alkyl, hydroxyC₁₋₄alkyl, phenyl, —CO—C₁₋₃alkoxy and—CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionallysubstituted; each of R_(1h) and R_(2h) independently is H, halogen, OH,COOH, or optionally halogeno substituted C₁₋₆alkyl or phenyl; R_(ah) isH or C₁₋₄alkyl optionally substituted by halogen and/OH; each R_(4h)independently is halogen, OH, COOH, C₁₋₄alkyl, S(O)_(0, 1 or2)C₁₋₃alkyl,C₁₋₃alkoxy, C₃₋₆cycloalkoxy, aryl or aralkoxy, wherein the alkylportions may optionally be substituted by 1-3 halogens; and each ofR_(h) and M has one of the significances as indicated for B and C,respectively, in WO03/062248A2

or a pharmacologically acceptable salt, solvate or hydrate thereof.

-   -   Compounds as disclosed in WO 04/103306A, WO 05/000833, WO        05/103309 or WO 05/113330, e.g. compounds of formula Xa or Xb

wherein

A_(k) is COOR_(5k), OPO(OR_(5k))₂, PO(OR_(5k))₂, SO₂OR_(5k),POR_(5k)OR_(5k) or 1H-tetrazol-5-yl, R_(5k) being H or C₁₋₆alkyl;

W_(k) is a bond, C₁₋₃alkylene or C₂₋₃alkenylene;

Y_(k) is C₆₋₁₀aryl or C₃₋₉heteroaryl, optionally substituted by 1 to 3radicals selected from halogene, OH, NO₂, C₁₋₆alkyl, C₁₋₆alkoxy;halo-substituted C₁₋₆alkyl and halo-substituted C₁₋₆alkoxy;

Z_(k) is a heterocyclic group as indicated in WO 04/103306A, e.g.azetidine;

R_(1k) is C₆₋₁₀aryl or C₃₋₉heteroaryl, optionally substituted byC₁₋₆alkyl, C₆₋₁₀aryl, C₆₋₁₀aryl C₁₋₄alkyl, C₃₋₉heteroaryl,C₃₋₉heteroarylC₁₋₄alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₄alkyl,C₃₋₈heterocycloalkyl or C₃₋₈heterocycloalkylC₁₋₄alkyl; wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl of R_(1k) may be substitutedby 1 to 5 groups selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy and halosubstituted-C₁₋₆alkyl or —C₁₋₆alkoxy;

R_(2k) is H, C₁₋₆alkyl, halo substituted C₁₋₆alkyl, C₂₋₆alkenyl orC₂₋₆alkynyl: and

each of R_(1k) or R_(4k), independently, is H, halogen, OH, C₁₋₆alkyl,C₁₋₆alkoxy or halo substituted C₁₋₆alkyl or C₁₋₆alkoxy;

and the N-oxide derivatives thereof or prodrugs thereof,

or a pharmacologically acceptable salt, solvate or hydrate thereof.

The compounds of formulae I to Xb may exist in free or salt form.Examples of pharmaceutically acceptable salts of the compounds of theformulae Ill to VIII include salts with inorganic acids, such ashydrochloride, hydrobromide and sulfate, salts with organic acids, suchas acetate, fumarate, maleate, benzoate, citrate, malate,methanesulfonate and benzenesulfonate salts, or, when appropriate, saltswith metals such as sodium, potassium, calcium and aluminium, salts withamines, such as triethylamine and salts with dibasic amino acids, suchas lysine. The compounds and salts of the combination of the presentinvention encompass hydrate and solvate forms.

Acyl as indicated above may be a residue R_(y)—CO— wherein R_(y) isC₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl or phenyl-C₁₋₄alkyl. Unless otherwisestated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.

Aryl may be phenyl or naphthyl, preferably phenyl.

When in the compounds of formula I the carbon chain as R₁ issubstituted, it is preferably substituted by halogen, nitro, amino,hydroxy or carboxy. When the carbon chain is interrupted by anoptionally substituted phenylene, the carbon chain is preferablyunsubstituted. When the phenylene moiety is substituted, it ispreferably substituted by halogen, nitro, amino, methoxy, hydroxy orcarboxy.

Preferred compounds of formula I are those wherein R₁ is C₁₃₋₂₀alkyl,optionally substituted by nitro, halogen, amino, hydroxy or carboxy,and, more preferably those wherein R₁ is phenylalkyl substituted byC₆₋₁₄-alkyl chain optionally substituted by halogen and the alkyl moietyis a C₁₋₆alkyl optionally substituted by hydroxy. More preferably, R₁ isphenyl-C₁₋₆alkyl substituted on the phenyl by a straight or branched,preferably straight, C₆₋₁₄alkyl chain. The C₆₋₁₄alkyl chain may be inortho, meta or para, preferably in para.

Preferably each of R₂ to R₅ is H.

In the above formula of VII “heterocyclic group” represents a 5- to 7membered heterocyclic group having 1 to 3 heteroatoms selected from S, Oand N. Examples of such heterocyclic groups include the heteroarylgroups indicated above, and heterocyclic compounds corresponding topartially or completely hydrogenated heteroaryl groups, e.g. furyl,thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl orpyrazolidinyl. Preferred heterocyclic groups are 5- or 6-memberedheteroaryl groups and the most preferred heterocyclic group is amorpholinyl, thiomorpholinyl or piperidinyl group.

A preferred compound of formula I is2-amino-2-tetradecyl-1,3-propanediol. A particularly preferred S1Preceptor agonist of formula III is FTY720, i.e.2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in apharmaceutically acceptable salt form (referred to hereinafter asCompound A), e.g. the hydrochloride, as shown:

A preferred compound of formula II is the one wherein each of R′₂ to R′₅is H and m is 4, i.e.2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol, infree form or in pharmaceutically acceptable salt form (referred tohereinafter as Compound B), e.g the hydrochloride.

A preferred compound of formula III is the one wherein W is CH₃, each ofR″₁ to R″₃ is H, Z₂ is ethylene, X is heptyloxy and Y is H, i.e.2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol, in free form or inpharmaceutically acceptable salt form (referred to hereinafter asCompound C), e.g. the hydrochloride. The R-enantiomer is particularlypreferred.

A preferred compound of formula IVa is the FTY720-phosphate (R_(2a) isH, R_(1a) is OH, X_(a) is O, R_(1a) and R_(1b) are OH). A preferredcompound of formula IVb is the Compound C-phosphate (R_(2a) is H, R_(3b)is OH, X_(a) is O, R_(1a) and R_(1b) are OH, Y_(a) is O and R_(4a) isheptyl). A preferred compound of formula V is Compound B-phosphate.

A preferred compound of formula VII is(2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbutan-1-ol.

A preferred compound of formula Xa is e.g.1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid, or a prodrug thereof.

It will be appreciated that the compounds as described herein may be thedirect active substances, or may be prodrugs. For example, the compoundsmay be phosphorylated forms.

Oral Formulations

The dosage form of a composition of the present invention, e.g. thefinal dosage form, may be a solid dosage form, e.g. a tablet. In anotherembodiment of the present invention the dosage form is granular, e.g.powder form and may comprise part of a suspension or gel. Another dosageforms may comprise of small multiparticulate pellets/beads. Other dosageforms may comprise a solid or granular composition which is soluble in aliquid to produce a liquid formulation prior to administration. Examplesof such formulations are soluble tablets, capsules and sachets. Thefinal liquid formulation may be consumed as a drink.

The oral route is often the most convenient route for drugadministration. This may be in the form of a standard tablet, aconventional orally disintegrating tablet, a lyophilized tablet, or athin film.

It has been found that compounds comprising a group of formula Y, e.g.amino-propane-1,3-diols, e.g. those that have S1P agonist activity, arenot easy to formulate. In particular, these are not easy to formulate ina solid oral formulation.

As such, the present inventors have surprisingly found that only alimited number of excipients are potentially feasible with such aminodiols.

The Maillard Reaction

The Maillard reaction is a chemical reaction between an amino acid and areducing sugar [Sugars that contain aldehyde groups that are oxidised tocarboxylic acids are classified as reducing sugars.

Reducing sugars include glucose, glyceraldehyde, lactose, arabinose andmaltose], usually requiring the addition of heat. Like caramelization,it is a form of non-enzymatic browning. The reactive carbonyl group ofthe sugar interacts with the nucleophilic amino group of the amino acid,and interesting but poorly characterized odor and flavor moleculesresult. This process accelerates in an alkaline environment because theamino groups do not neutralize. This reaction is the basis of theflavouring industry, since the type of amino acid determines theresulting flavour.

The potentially feasible excipients are classified into e.g. fillers,binders, disintegrants, lubricants, flow regulators, plastisizers, andmatrix formers. Some excipients can be listed in more than one class.

Typical ranges found in a final formulation comprising a compound asdescribed herein are as follows:

Fillers: 10-97%

Binders: 1-15%

Disintegrants: 1-15%

Lubricants: 0.5-2%

Flow regulators: 0.5-3%

Matrix formers: 3-50%

Plastisizers: 5-30%

Flavoring agents: 1-20%

Sweeteners: 1-20%

The present invention therefore relates to stable blends comprising acompound having a group of formula Y and at least one other excipient.

The compound having a group of formula Y may, in one embodiment, bemixed together with one or more of the following excipients:

(a) Fillers selected from Lactose monohydrate, Lactose anhydrous, Maizestarch, Mannitol, Xylitol, sorbitol, sucrose, Microcrystallinecellulose, e.g. Avicel PH101, Dibasic calcium phosphate, Maltodextrin,gelatin, e.g. DE 12

and/or

(b) Binders selected from HPMC, e.g. 3cPs, L-HPC, e.g. HP-CelluloseLH-22, Povidone.

and/or

(c) Disintegrants selected from Maize starch, Crospovidone,Croscarmellose sodium, Sodium carboxymethylstarch e.g. Primojel,pregelatinized starch, e.g. Starch 1500 (Sta RX), calcium silicate

and/or

(d) Lubricants selected from Hydrogenated e.g. ricinoleic, castor oil,e.g. Cutina, magnesium stearate, calcium stearate, zinc stearate,mineral oil, silicone fluid, sodium lauryl sulfate, L-leucine, sodiumstearyl fumarate,

and/or

(e) Flow regulators selected from Aerosil 200Colloidal silicone dioxide,e.g. Aerosil 200, Talc

and/or

(f) Matrix formers selected from Hydroxypropyl methyl cellulose,Hydroxypropyl cellulose, Methyl cellulose, Ethyl cellulose, Pullulan,Starch, e.g. Pure Cote, Povidone

and/or

(g) Plastisizers selected from PEG 400, Dibutyl sebacate, Sorbitol

and/or

(h) Flavoring agents selected from Menthol, tutti fruti

and/or

-   -   (i) Sweeteners selected from Sucralose, Sodium saccharine.

Fillers are preferably selected from Fillers selected from Lactosemonohydrate, Lactose anhydrous, Maize starch, Xylitol, sorbitol,sucrose, Microcrystalline cellulose, e.g. Avicel PH101, Dibasic calciumphosphate, Maltodextrin and gelatin.

According to one embodiment of the invention preferred fubricants areselected from magnesium stearate and calcium stearate.

In a second embodiment, the present invention relates to a binary blendcomprising a compound having a group of formula Y and one excipientselected from:

Sorbitol, Xylitol, dicalcium phosphate, Lactose, microcrystallinecellulose, HPMC, HPC, Crospovidone, croscarmellose sodium, starch,preferably an hydrous, calcium silicate, colloidal silicone dioxide,talc, magnesium stearate, calcium stearate.

Preferably, no moisture is present.

In particular, the excipients are selected from:

Dicalcium phosphate, HPC, crospovidone, calcium silicate, magnesiumstearate.

In particular, the formulation or blend of the present invention doesnot comprise a reducing sugar, e.g glucose, glyceraldehyde, lactose,arabinose and maltose.

In a further preference, the formulation or blend of the presentinvention does not comprise PEG, stearic acid,

Where necessary, stabilizers may be added to increase or decrease thepH. By modifying the pH, the composition may be adapted to optimize thereduction of likelihood of a malliard reaction, or other side reactionstaking place. An example of a stabilizer is citric acid.

In a preferred embodiment of the compositions of the present inventionare binary blends, i.e. a mixture of a compound comprising a group offormula Y and one excipient as listed herein.

A particular advantage of the stable binary blends as disclosed hereinis that they may be transported and stored prior to final formulation,without forming degradation products. The blends of the presentinvention, e.g. binary blends, therefore provide a commercially viableoption for storing the S1P modulator as described herein in stableconditions.

Prior to the surprising findings of the present invention, theinstability of the compounds comprising a group Y would not have beenable to be safely stored, without the possibility of impurities beingformed. With the present invention, the skilled person is now shownwhich excipients may be used with the S1P modulators for storage and,most importantly, which excipients may be used to reduce the risk ofimpurities contaminating a final drug product, such impurities beingformed by a malliard reaction.

Levels of Impurities Tolerated:

Compositions of the present invention, e.g. binary blends and/or finaldosage forms, are preferably free from impurities. It will be understoodthat the level of impurities tolerated will be judged usingpharmaceutically acceptable standards.

However, it is also understood the pharmaceutical standards may onlyapply to a final dosage form, i.e. the final product. The presentinvention, in a preferred embodiment provides binary blends containingan S1P receptor modulator as definated herein, i.e. a compoundcomprising a group of formula Y, which are low, e.g. free, ofimpurities. Preferably the binary blends of the present invention meetthe following criteria for level of impurities:

-   -   No more than 4.5 wt % of impurities and/or but no more than 2 wt        % for an individual impurity.    -   Preferably, impurities are at 2 wt % or lower with no individual        impurity being more than 0.5 wt %

The “wt %” measurements above are indicators of amount of impuritiestolerated. The term “wt %” means the percentage in relation to theamount of the whole formulation, for example 4 wt % means 4 mg in a 100mg tablet.

Example of Impurity Tolerances, Using the Compound FTY720 as a Reference

There are three qualified degradation products observed in a dosageform: acetyl amide, palmitate amide and stearate amide.

The mechanism for the formation of these degradation products ispostulated to be due to a nucleophilic attack of the primary amine ofthe FTY720 molecule at the carbonyl carbon of the acetic, palmitic orstearic acid.

Based on tox qualification study, the three primary degradationproducts, acetyl amide, palmitate amide and stearate amide werequalified at levels of 4.6%, 4.5% and 4.8%, respectively.

In order to adequately control the quality and efficacy of the finaldosage product each qualified degradation product was assigned aspecification of equal to or less than 2.0% of label strength.

The specified degradation products were assigned a specification ofequal to or less than 1.0% of label strength.

The unspecified degradation products were assigned a specification ofequal to or less than 0.5% of label strength as per the Novartis drugproduct purity policy.

The sum of all the degradation products above the limit of quantitation(0.1% label strength) was set at equal or less than a total of 4.5%.

FTY720: An Example of a Compound Comprising a Group of Formula Y:

A chemical stability program using binary mixtures of FTY720 andexcipients (1% drug substance was stored for 1 month in closed vials at50° C.) was performed using FTY720 drug substance.

General method to prepare binary mixtures:

1. 10 mg drug substance and 1000 mg excipient were filled into a glassvial (=binary mixture).

2. The closed vials were stored for 1 month at 50° C.

The analytical characterization was performed using gradient HPLC withUV detection. For the analysis, the stored samples were dissolved in 40ml of 0.0005N hydrochloric acid in isopropanol and stirred with amagnetic stirrer for 30 minutes. This solution was centrifuged and analiquot of the clear supernatant was used as the test solution.

The limit of quantitation (loq) of the method was 0.1%. The rel.standard deviation s_(rel) of the assay determinations was ≦2%.

Apparatus HPLC system with gradient capability, autosampler and UVdetector Column Waters Xterra ™ MS C₈ Length 50 mm, internal diameter4.6 mm, particle size 2.5 μm, Part number 186000603. Chromatographicconditions Mobile phase A 100 mM NaClO₄ buffer, pH 2.8:methanol = 93:7(v/v) Mobile phase B Acetonitrile Time [min.] Phase A [%] Phase B [%]Gradient program 0 70 30 (linear) 1.0 70 30 15.0 58 42 28.0 5 95 30.0 595 30.1 70 30 35.0 70 30 Flow rate 1.5 ml/min Detection UV detection at215 nm Column temperature 30° C. Auto-sampler Ambient TemperatureInjection volume 10 μl Run time 35 min

The tables below provide a list of potentially feasible excipientsincluding the results of the stability program.

EXAMPLE 1 FTY720 Stability Test with Selected Fillers

Excipient Assay in % Σ impurities in % Lactose anhydrous 101.4 0.0 Maizestarch 102.2 0.0 Mannitol 102.3 0.0 Mannitol granulated (SD 200) 99.50.3 Avicel 97.9 0.2 Citric acid + Mannitol (10 + 90) 102.4 0.0 Sodiumhydrogen carbonate + Mannitol 102.7 0.0 (10 + 90)

EXAMPLE 2 FTY720 Stability Test with Selected Binders

Excipient Assay in % Σ impurities in % HPMC 3cPs 97.8 0.0 HP-CelluloseLH-22 99.8 0.4

EXAMPLE 3 FTY720 Stability Test with Selected Disintegrants

Excipient Assay in % Σ impurities in % Maize starch 102.2 0.0Crosscarmellose sodium 102.4 0.0 Sodium carboxymethylstarch (Primojel)103.2 0.0 Starch 1500 (Sta RX) 101.3 0.0

EXAMPLE 4 FTY720 Stability Test with Selected Lubricants

Excipient Assay in % Σ impurities in % Hydrogenated ricinoleic oil(Cutina) 103.6 0.0 Mg stearate + Manitol (1 + 99) 103.5 0.5

EXAMPLE 5 FTY720 Stability Test with Selected Flow Regulators

Excipient Assay in % Σ impurities in % Aerosil 200 101.5 0.6

EXAMPLE 6 FTY720 Stability Test with Selected Matrix Formers

Excipient Assay in % Σ impurities in % Hydroxypropyl methyl cellulose97.8 0.0 Hydroxypropyl cellulose 99.8 0.4 Methyl cellulose — — Ethylcellulose — — Pullulan — — Starch, e.g. Pure Cote 102.2  0.0 Povidone95.4 0.5

Polymers having different molecular weights may be used in the sameformulation, e.g. having a low and a high molecular weight, i.e. one canuse a mixture of e.g. cellulose type polymers having a low and a high MWto provide for different properties.

EXAMPLE 7 FTY720 Stability Test with Selected Plastisizers

Excipient Assay in % Σ impurities in % PEG 400 — — Dibutyl sebacate — —Sorbitol — —

EXAMPLE 8 FTY720 Stability Test with Selected Flavoring Agents

Excipient Assay in % Σ impurities in % Menthol — — Tutti frutti

EXAMPLE 9 FTY720 Stability Test with Selected Sweeteners

Excipient Assay in % Σ impurities in % Sucralose — — Sodium saccharine ——

EXAMPLE 10 Non-Feasible Excipients

An example of a non-feasible excipient is shown below. The method toprepare the binary mixtures and the analytical characterization are thesame as describe before.

Excipient Assay in % Σ impurities in % Glycerylbehenat 96.2 >2(Compritol)

EXAMPLE 10 S1P Assays

The binding affinity of S1P receptor modulators to individual human S1Preceptors may be determined in following assay:

S1P receptor modulator activities of compounds are tested on the humanS1P receptors S1P₁, S1P₂, S1P₃, S1P₄ and S1P₅. Functional receptoractivation is assessed by quantifying compound induced GTP [γ-³⁵S]binding to membrane protein prepared from transfected CHO or RH7777cells stably expressing the appropriate human S1P receptor. The assaytechnology used is SPA (scintillation proximity based assay). Briefly,DMSO dissolved compounds are serially diluted and added to SPA-bead(Amersham-Pharmacia) immobilised S1P receptor expressing membraneprotein (10-20 μg/well) in the presence of 50 mM Hepes, 100 mM NaCl, 10mM MgCl₂, 10 μM GDP, 0.1% fat free BSA and 0.2 nM GTP [γ-³⁵S] (1200Ci/mmol). After incubation in 96 well microtiterplates at RT for 120min, unbound GTP [γ-³⁵S] is separated by a centrifugation step.Luminescence of SPA beads triggered by membrane bound GTP [γ-³⁵S] isquantified with a TOPcount plate reader (Packard). EC₅₀s are calculatedusing standard curve fitting software. In this assay, the S1P receptormodulators preferably have a binding affinity to S1P receptor<50 nM.

Preferred S1P receptor modulators are e.g. compounds which in additionto their S1P binding properties also have accelerating lymphocyte homingproperties, e.g. compounds which elicit a lymphopenia resulting from are-distribution, preferably reversible, of lymphocytes from circulationto secondary lymphatic tissue, without evoking a generalizedimmunosuppression. Naïve cells are sequestered; CD4 and CD8 T-cells andB-cells from the blood are stimulated to migrate into lymph nodes (LN)and Peyer's patches (PP).

The lymphocyte homing property may be measured in following BloodLymphocyte Depletion assay:

A S1P receptor modulator or the vehicle is administered orally by gavageto rats. Tail blood for hematological monitoring is obtained on day −1to give the baseline individual values, and at 2, 6, 24, 48 and 72 hoursafter application. In this assay, the S1P receptor agonist or modulatordepletes peripheral blood lymphocytes, e.g. by 50%, when administered ata dose of e.g. <20 mg/kg.

Final Product Manufacture:

The manufacture of final pharmaceutical products may be carried outusing conventional techniques. Examples of such techniques are describedbelow, by way of example.

Compressed Tablets

Compressed tablets are exerted to great pressure in order to compact thematerial. If a sufficiently homogeneous mix of components cannot beobtained with simple mixing, the ingredients must be granulated prior tocompression to ensure an even distribution of the active compound in thefinal tablet. Two basic techniques are used to prepare powders forgranulation into a tablet: wet granulation and dry granulation.

Powders that can be mixed well and therefore do not require granulationcan be compressed in to a tablet through a technique called DirectCompression.

Lyophilised Tablets

These tablets may be manufactured by way of creating a suspensioncontaining the active ingredient and other excipients, for exampleGelatin in an amount, for example, of about 3 wt %, structure formingagents, such as mannitol or sorbitol, for example and in an amount, forexample, of about 1.5 wt %, sweeteners and flavouring agents.

An example of a lyophilised tablet formulation is provided below:

The Gelatin/Mannitol solution is cooled to 23° C. and mixed with theactive substance. The total solid content is preferably less than 50%.The suspension is then cooled to 15° C. to prevent sedimentation of thesuspension before the start of lyophilisation.

Thin Films

The compositions of the present invention may be further mixed withadditional excipients to form final products. The final products may bemade from the binary compositions using standard techniques, such as theones below:

Possible manufacturing comprises casting, drawing, extrusion orcoating/lamination processes:

Casting is a manufacturing process by which the drug/excipient mixtureis introduced into a mold, allowed to solidify within the mold, and thenejected or broken out to make the individual thin film.

Drawing produces a roll by pulling on a molten drug/excipient mixtureuntil it increases in length. This is typically accompanied by athinning out of the material. The single units are then cut or punchedout of these roles and packed, e.g. into pouches.

Extrusion creates rolls by pushing and/or drawing through a die of thedesired profile shape. Extrusion may be continuous (producingindefinitely long material) or semi-continuous (producing many shortpieces). The single units are then cut or punched out of these roles andpacked, e.g. into pouches.

Coating/lamination could be described as manufacturing a laminate firstby coating and lamination. The resulting roll is then splitted intosmaller rolls. The single units are then cut or punched out of theseroles and packed, e.g. into pouches.

According to the invention, the compositions of the present invention,e.g. the final dosage form, are useful for:

a) treatment and prevention of organ or tissue transplant rejection, forexample for the treatment of the recipients of heart, lung, combinedheart-lung, liver, kidney, pancreatic, skin or corneal transplants, andthe prevention of graft-versus-host disease, such as sometimes occursfollowing bone marrow transplantation; particularly in the treatment ofacute or chronic allo- and xenograft rejection or in the transplantationof insulin producing cells, e.g. pancreatic islet cells;

b) treatment and prevention of autoimmune disease or of inflammatoryconditions, e.g. multiple sclerosis, arthritis (for example rheumatoidarthritis), inflammatory bowel disease, hepatitis, etc.;

c) treatment and prevention of viral myocarditis and viral diseasescaused by viral mycocarditis, including hepatitis and AIDS.

d) treatment and prevention of cancer, e.g. solid tumors, carcinoma,e.g. for preventing metastatic spread of tumours or for preventing orinhibiting growth of micrometastasis

By “solid tumors” are meant tumors and/or metastasis (wherever located)other than lymphatic cancer, e.g. brain and other central nervous systemtumors (eg. tumors of the meninges, brain, spinal cord, cranial nervesand other parts of central nervous system, e.g. glioblastomas or medullablastomas); head and/or neck cancer; breast tumors; circulatory systemtumors (e.g. heart, mediastinum and pleura, and other intrathoracicorgans, vascular tumors and tumor-associated vascular tissue); excretorysystem tumors (e.g. kidney, renal pelvis, ureter, bladder, other andunspecified urinary organs); gastrointestinal tract tumors (e.g.oesophagus, stomach, small intestine, colon, colorectal, rectosigmoidjunction, rectum, anus and anal canal), tumors involving the liver andintrahepatic bile ducts, gall bladder, other and unspecified parts ofbiliary tract, pancreas, other and digestive organs); oral cavity (lip,tongue, gum, floor of mouth, palate, and other parts of mouth, parotidgland, and other parts of the salivary glands, tonsil, oropharynx,nasopharynx, pyriform sinus, hypopharynx, and other sites in the lip,oral cavity and pharynx); reproductive system tumors (e.g. vulva,vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sitesassociated with female genital organs, placenta, penis, prostate,testis, and other sites associated with male genital organs);respiratory tract tumors (e.g. nasal cavity and middle ear, accessorysinuses, larynx, trachea, bronchus and lung, e.g. small cell lung canceror non-small cell lung cancer); skeletal system tumors (e.g. bone andarticular cartilage of limbs, bone articular cartilage and other sites);skin tumors (e.g. malignant melanoma of the skin, non-melanoma skincancer, basal cell carcinoma of skin, squamous cell carcinoma of skin,mesothelioma, Kaposi's sarcoma); and tumors involving other tissuesincluding peripheral nerves and autonomic nervous system, connective andsoft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid,adrenal gland and other endocrine glands and related structures,secondary and unspecified malignant neoplasm of lymph nodes, secondarymalignant neoplasm of respiratory and digestive systems and secondarymalignant neoplasm of other sites.

Where hereinbefore and subsequently a tumor, a tumor disease, acarcinoma or a cancer is mentioned, also metastasis in the originalorgan or tissue and/or in any other location are implied alternativelyor in addition, whatever the location of the tumor and/or metastasis is.

Accordingly, in further aspects the present invention provides:

1. A composition as defined above, for use in treating or preventing adisease or condition as defined above.

2. A method of treating a subject in need of immunomodulation,comprising administering to the subject an effective amount of acomposition as defined above.

3. A method of treating or preventing a disease or condition as definedabove, comprising administering to the subject a composition as definedabove.

4. Use of a pharmaceutical composition as defined above for thepreparation of a medicament for the prevention or treatment of a diseaseor condition as defined above.

1. A stable composition comprising: (i) a compound comprising a group offormula Y

wherein Z is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, phenylsubstituted by OH, C₁₋₆alkyl substituted by 1 to 3 substituents selectedfrom the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenylsubstituted by OH, or CH₂—R_(4z) wherein R_(4z) is OH, acyloxy or aresidue of formula (a)

wherein Z₁ is a direct bond or O; each of R_(5z) and R_(6z),independently, is H, or C₁₋₄alkyl optionally substituted by 1, 2 or 3halogen atoms; R_(1z) is OH, acyloxy or a residue of formula (a); andeach of R_(2z) and R_(3z) independently, is H, C₁₋₄alkyl or acyl; and(ii) one or more of the following excipients: (a) one or more Fillersselected from the group consisting of Lactose monohydrate, Lactoseanhydrous, Maize starch, Mannitol, Xylitol, sorbitol, sucrose, andMicrocrystalline cellulose; (b) one or more Binders selected from thegroup consisting of HPMC, L-HPC, Povidone, and HPC; (c) one or moreDisintegrants selected from the group consisting of Maize starch,Crospovidone, Croscarmellose sodium, Sodium carboxymethylstarch,pregelatinized starch, and calcium silicate; (d) one or more Lubricantsselected from the group consisting of Hydrogenated castor oil, Glycerolbehenate, magnesium stearate, calcium stearate, zinc stearate, mineraloil, silicone fluid, sodium lauryl sulfate, L-leucine, and sodiumstearyl fumarate; (e) one or more Flow regulators selected from thegroup consisting of Colloidal silicone dioxide, and Talc; (f) one ormore Matrix formers selected from the group consisting of Hydroxypropylmethyl cellulose, Hydroxypropyl cellulose, Methyl cellulose, Ethylcellulose, Pullulan, Starch, e.g. Pure Cote, and Povidone; (g) one ormore Plastisizers selected from the group consisting of PEG 400, Dibutylsebacate, and Sorbitol; (h) one or more Flavoring agents selected fromthe group consisting of Menthol, and tutti fruit; and (i) one or moreSweeteners selected from the group consisting of Sucralose, and Sodiumsaccharine.
 2. The composition of claim 1, wherein the excipients areselected from the group consisting of Sorbitol, Xylitol, dicalciumphosphate, Lactose, microcrystalline cellulose, HPMC, HPC, Crospovidone,croscarmellose sodium, starch, calcium silicate, colloidal siliconedioxide, talc, magnesium stearate and calcium stearate.
 3. Thecomposition of claim 1, wherein the composition comprises a binary blendconsisting of a compound comprising a group of formula Y and oneexcipient.
 4. The composition of claim 1, wherein the compoundcontaining a group of formula Y is selected from the group consisting of2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol (FTY720) in freeform, a pharmaceutically acceptable salt thereof, FTY720-phosphate,1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid, and a prodrug thereof.
 5. The composition of claim 1, wherein thelevel of impurities is not more than 4.5 wt % and/or no more than 2 wt %for an individual impurity.
 6. The composition of claim 1 for use as apharmaceutical.
 7. The composition of claim 1 in the form of a tablet orcapsule.
 8. A method for the treatment of organ or tissue transplantrejection, graft versus host disease, autoimmune diseases, inflammatoryconditions, viral myocarditis, viral diseases caused by viralmyocarditis or cancers comprising administration of the composition ofclaim
 1. 9. The method of claim 8 for the treatment of an autoimmunedisease.
 10. The method of claim 8 for the treatment of multiplesclerosis.
 11. The method of claim 8 wherein the compound of formula Yis selected from the group consisting of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) in free form, a pharmaceuticallyacceptable salt thereof, FTY720-phosphate,1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid, and a prodrug thereof.
 12. The composition of claim 4 wherein thecompound containing a group of formula Y is FTY720 in free form or apharmaceutically acceptable salt thereof.
 13. The method of claim 11wherein the compound containing a group of formula Y is FTY720 in freeform or a pharmaceutically acceptable salt thereof.